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The AP-1 transcription factor Batf controls TH17 differentiation

Abstract

Activator protein 1 (AP-1, also known as JUN) transcription factors are dimers of JUN, FOS, MAF and activating transcription factor (ATF) family proteins characterized by basic region and leucine zipper domains1. Many AP-1 proteins contain defined transcriptional activation domains, but BATF and the closely related BATF3 (refs 2, 3) contain only a basic region and leucine zipper, and are considered to be inhibitors of AP-1 activity3,4,5,6,7,8. Here we show that Batf is required for the differentiation of IL17-producing T helper (TH17) cells9. TH17 cells comprise a CD4+ T-cell subset that coordinates inflammatory responses in host defence but is pathogenic in autoimmunity10,11,12,13. Batf-/- mice have normal TH1 and TH2 differentiation, but show a defect in TH17 differentiation, and are resistant to experimental autoimmune encephalomyelitis. Batf-/- T cells fail to induce known factors required for TH17 differentiation, such as RORγt11 (encoded by Rorc) and the cytokine IL21 (refs 14–17). Neither the addition of IL21 nor the overexpression of RORγt fully restores IL17 production in Batf-/- T cells. The Il17 promoter is BATF-responsive, and after TH17 differentiation, BATF binds conserved intergenic elements in the Il17a–Il17f locus and to the Il17, Il21 and Il22 (ref. 18) promoters. These results demonstrate that the AP-1 protein BATF has a critical role in TH17 differentiation.

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Figure 1: Loss of IL17 production in Batf -/- T cells.
Figure 2: Batf -/- mice are resistant to EAE.
Figure 3: BATF controls several T H 17-associated genes.
Figure 4: BATF directly regulates IL17 expression.

Accession codes

Primary accessions

ArrayExpress

Data deposits

Microarray data are available at Array Express (http://www.ebi.ac.uk/arrayexpress/) under the accession numbers E-MEXP-1518, E-MEXP-2152 and E-MEXP-2153.

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Acknowledgements

We thank R. Lallone for anti-BATF antibody preparation, and B. Sleckman for Cre-expressing adenovirus. This work was supported by the Howard Hughes Medical Institute (K.M.M.), and grants from the National Institutes of Health HG00249 and training grant GM07200 (G.D.S.), AI035783 (C.T.W.), AR049293 (R.D.H.), and from Daiichi-Sankyo Co. Ltd (C.T.W.).

Author Contributions B.U.S. generated Batf-/- mice, designed and analysed the experiments, interpreted results and wrote the manuscript. K.H. constructed the targeting vector and probes, transgenic vector, and recombinant BATF. W.I. helped with retroviral expression experiments. W.-L.L. helped with reverse-strand reporter analysis. W.A.-E.S. helped with mouse generation. B.S. helped with EMSA analysis. G.S. and G.D.S. performed bioinformatics analysis for the BATF binding elements. J.S. and J.H.R. helped with EAE experiments. R.M., R.D.H. and C.T.W. performed ChIP experiments. T.L.M. and S.C. performed confocal microscopy for BATF. K.M.M. directed the study and wrote the manuscript.

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Correspondence to Kenneth M. Murphy.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-14 with Legends, Supplementary Tables 1, 5-6, Supplementary Methods and Supplementary References. (PDF 1930 kb)

Supplementary Table 2

This file contains microarray data in Excel format accompanying Figure 3c. (XLS 27 kb)

Supplementary Table 3

This file contains microarray data in Excel format accompanying Supplementary Figure 9a. (XLS 1 kb)

Supplementary Table 4

This file contains Gene ChIP data in Excel format accompanying Supplementary Figure 9b. (XLS 1 kb)

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Schraml, B., Hildner, K., Ise, W. et al. The AP-1 transcription factor Batf controls TH17 differentiation. Nature 460, 405–409 (2009). https://doi.org/10.1038/nature08114

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